Chromosome aberrations and oncogenes in human cancer

The combined application of cytogenetic and molecular genetic techniques has elucidated the involvement of cellular oncogenes in tumor specific chromosomal abnormalities. Although these studies further underline the fundamental role of chromosomal abnormalities in tumor-development, as yet virtually nothing is known of the generation of these aberrations. DNA sequence analysis of BL and CML specific chromosomal breakpoint regions revealed no clue to a possible translocation mechanism. However, a report by Fialkow et al. (1981) indicates that in CML, the acquisition of the Ph1 chromosome is preceded by an initial phase of marked genetic instability. A similar phase of genetic instability of Ig or TCR loci may occur during the process of somatic rearrangements of these genes. During these phases, presumably various translocations occur and those with a selective growth advantage will eventually result in a clinically apparent leukemia. It has been suggested that fragile sites may act as predisposing factors for certain specific chromosomal rearrangements (Yunis and Soreng, 1984~ LeBeau and Rowley, 1984). The chromosomal location of a number of these fragile sites coincides with specific chromosomal breakpoint regions. Furthermore, leukemic patients were identified as carriers of a fragile site at the observed chromosomal breakpoint (Yunis, 1983~ LeBeau, 1986). Although several genes, among which some oncogenes, have been mapped to an identical chromosomal region as a fragile site, at present the exact nature and function of the genes located at these sites remains an enigma. Molecular techniques as Southern blotting and chromosomal walking have demonstrated in a few tumor specific aberrations the localization of (putative) oncogenes in the direct vicinity of the chromosomal breakpoint region. However, in other tumor specific aberrations the exact nature of the association between cytogenetic changes and alterations at the DNA or gene level remains obscure. The application of new techniques as Pulsed Field Gradient (PFG) gel electrophoresis (Schwartz and Cantor, 1984~ Carle and Olson, 1984), which allows the separation of large (50-2000 kb) DNA fragments could help to corroborate a possible involvement of oncogenes in these cases. Furthermore, the use of PFG gels could lead to the detection of deletions which are not visible at the cytogenetic level. An example concerning deletions of part of chromosome lp32, which resulted in the activation of the trk oncogene in a human colon carcinoma has recently been reported (Martin-Zanca et al., 1986)

Etiology of Esophageal Atresia and Tracheoesophageal Fistula: “Mind the Gap”

Esophageal atresia and tracheoesophageal fistula (EA/TEF) are major congenital malformations affecting 1:3500 live births. Current research efforts are focused on understanding the etiology of these defects. We describe well-known animal models, human syndromes, and associations involving EA/TEF, indicating its etiologically heterogeneous nature. Recent advances in genotyping technology and in knowledge of human genetic variation will improve clinical counseling on etiologic factors. This review provides a clinical summary of environmental and genetic factors involved in EA/TEF

Generation of three iPSC lines from two patients with heterozygous FOXF1 mutations associated to Alveolar Capillary Dysplasia with Misalignment of the Pulmonary Veins

Diagnosing Alveolar Capillary Dysplasia with Misalignment of the Pulmonary Veins (ACD/MPV) based on a genetic alteration in the FOXF1 gene, is complicated by the poor understanding of the causal relation between FOXF1 variants and the ACD/MPV phenotype. Here, we report the generation of human iPSC lines from two ACD/MPV patients, each carrying a different heterozygous FOXF1 mutation, which enables disease modeling for further research on the effect of FOXF1 variants in vitro. The iPSC lines were generated from skin fibroblasts using the non-integrating Sendai virus. The lines expressed pluripotency genes, retained the heterozygous mutation and were capable of trilineage differentiation

Genetics of Uveal Melanoma and Cutaneous Melanoma: Two of a Kind?

Cutaneous melanoma and uveal melanoma both derive from melanocytes but show remarkable differences in tumorigenesis, mode of metastatic spread, genetic alterations, and therapeutic response. In this review we discuss the differences and similarities along with the genetic research techniques available and the contribution to our current understanding of melanoma. The several chromosomal aberrations already identified prove to be very strong predictors of decreased survival in CM and UM patients. Especially in UM, where the overall risk of metastasis is high (45%), genetic research might aid clinicians in selecting high-risk patients for future systemic adjuvant therapies

Dose fractionation effects in primary and metastatic human uveal melanoma cell lines

PURPOSE: To investigate the effects of split-dose irradiation on primary and metastatic uveal melanoma cell lines, with a clonogenic survival assay. METHODS: Appropriate cell concentrations of four primary and four metastatic human uveal melanoma cell lines were cultured for irradiation with single doses and with two equal fractions separated by 5 hours. After irradiation, colony formation was allowed for 7 to 21 days. Two cutaneous melanomas were also tested for comparison. All survival curves were analyzed using the linear quadratic (LQ) model. Specific parameters for the intrinsic radiosensitivity (alpha-component, SF2), for the capacity of repair of DNA damage (beta-component), as well as the alpha/beta ratio were calculated. RESULTS: After single-dose irradiation a wide range in the values of the alpha- and beta-component was obtained for both primary and metastatic uveal melanomas, which resulted in a wide range of alpha/beta ratios. In contrast, calculations based on split-dose data, with which the beta-component could be estimated independent of the alpha-component, indicated that estimates for the capacity of sublethal DNA damage repair was very similar in all cell lines. This indicated that intrinsic factors dominated the radiosensitivity of these cell lines. Split-dose irradiation had little influence on the intrinsic radiosensitivity (alpha-component), but cell survival increased for all cell lines. For the two cutaneous melanomas comparable split-dose results were obtained. CONCLUSIONS: For both primary and metastatic uveal melanoma cell lines, data from single and fractionated doses indicate large variations in radiosensitivity, which are mainly dominated by the intrinsic radiosensitivities. Doses of approximately 8 Gy in five fractions would be sufficient to eradicate 10(9) cells (approximately 1 cm3) of the most radioresistant tumor cell lines, but this schedule is an overkill for the radiosensitive tumor cell lines. Based on specific morphologic and histologic tumor markers, more individualized dose fractionation schedules could improve the therapeutic ratio for uveal melanomas

Uveal melanoma modeling in mice and zebrafish

Despite extensive research and refined therapeutic options, the survival for metastasized uveal melanoma (UM) patients has not improved significantly. UM, a malignant tumor originating from melanocytes in the uveal tract, can be asymptomatic and small tumors may be detected only during routine ophthalmic exams; making early detection and treatment difficult. UM is the result of a number of characteristic somatic alterations which are associated with prognosis. Although UM morphology and biology have been extensively studied, there are significant gaps in our understanding of the early stages of UM tumor evolution and effective treatment to prevent metastatic disease remain elusive. A better understanding of the mechanisms that enable UM cells to thrive and successfully metastasize is crucial to improve treatment efficacy and survival rates. For more than forty years, animal models have been used to investigate the biology of UM. This has led to a number of essential mechanisms and pathways involved in UM aetiology. These models have also been used to evaluate the effectiveness of various drugs and treatment protocols. Here, we provide an overview of the molecular mechanisms and pharmacological studies using mouse and zebrafish UM models. Finally, we highlight promising therapeutics and discuss future considerations using UM models such as optimal inoculation sites, use of BAP1mut-cell lines and the rise of zebrafish models.</p

Uveal melanoma modeling in mice and zebrafish

Despite extensive research and refined therapeutic options, the survival for metastasized uveal melanoma (UM) patients has not improved significantly. UM, a malignant tumor originating from melanocytes in the uveal tract, can be asymptomatic and small tumors may be detected only during routine ophthalmic exams; making early detection and treatment difficult. UM is the result of a number of characteristic somatic alterations which are associated with prognosis. Although UM morphology and biology have been extensively studied, there are significant gaps in our understanding of the early stages of UM tumor evolution and effective treatment to prevent metastatic disease remain elusive. A better understanding of the mechanisms that enable UM cells to thrive and successfully metastasize is crucial to improve treatment efficacy and survival rates. For more than forty years, animal models have been used to investigate the biology of UM. This has led to a number of essential mechanisms and pathways involved in UM aetiology. These models have also been used to evaluate the effectiveness of various drugs and treatment protocols. Here, we provide an overview of the molecular mechanisms and pharmacological studies using mouse and zebrafish UM models. Finally, we highlight promising therapeutics and discuss future considerations using UM models such as optimal inoculation sites, use of BAP1mut-cell lines and the rise of zebrafish models.</p